The 'Western diet' which is characterized by high saturated fat and high glycemic index foods (high diet) is a risk factor for Alzheimer's disease (AD). However, we have found paradoxically that experimental feeding with a Western style high diet acutely improves cognition in APOE E4 carriers, who are at increased risk for AD. The purpose of this project is to examine mechanisms that underlie this response. Based on known intrinsic differences in brain chemistry in E4 carriers, we hypothesize that in this group, a high meal will result in increased brain transport of lipids and insulin, increased ApoE lipidation, increased brain amyloid clearance, and ultimately improved cognition. We will test these hypotheses by conducting a controlled meal challenge in a crossover design in older adults with both a high meal, as well as a meal low in saturated fat and glycemic index foods (low). After the meal, participants will undergo cognitive testing and collection of blood and spinal fluid for analysis of lipids, insulin, and known AD biomarkers. This work will contribute to our broader understanding about the risks of diet and AD, and how APOE genotype moderates that risk. In addition to advancing our understanding about AD pathogenesis, this career development award will give me the necessary tools to become an independent clinical investigator in the field of metabolism and Alzheimer's disease.